Bach Horacio, Papavinasasundaram Kadamba G, Wong Dennis, Hmama Zakaria, Av-Gay Yossef
Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia V5Z 3J5, Canada.
Cell Host Microbe. 2008 May 15;3(5):316-22. doi: 10.1016/j.chom.2008.03.008.
Entry into host macrophages and evasion of intracellular destruction mechanisms, including phagosome-lysosome fusion, are critical elements of Mycobacterium tuberculosis (Mtb) pathogenesis. To achieve this, the Mtb genome encodes several proteins that modify host signaling pathways. PtpA, a low-molecular weight tyrosine phosphatase, is a secreted Mtb protein of unknown function. The lack of tyrosine kinases in the Mtb genome suggests that PtpA may modulate host tyrosine phosphorylated protein(s). We report that a genetic deletion of ptpA attenuates Mtb growth in human macrophages, and expression of PtpA-neutralizing antibodies simulated this effect. We identify VPS33B, a regulator of membrane fusion, as a PtpA substrate. VPS33B and PtpA colocalize in Mtb-infected human macrophages. PtpA secretion combined with active-phosphorylated VPS33B inhibited phagosome-lysosome fusion, a process arrested in Mtb infections. These results demonstrate that PtpA is essential for Mtb intracellular persistence and identify a key host regulatory pathway that is inactivated by Mtb.
进入宿主巨噬细胞并逃避细胞内破坏机制，包括吞噬体-溶酶体融合，是结核分枝杆菌（Mtb）发病机制的关键要素。为实现这一点，Mtb基因组编码了几种可改变宿主信号通路的蛋白质。PtpA是一种低分子量酪氨酸磷酸酶，是一种功能未知的分泌型Mtb蛋白。Mtb基因组中缺乏酪氨酸激酶表明PtpA可能调节宿主酪氨酸磷酸化蛋白。我们报道ptpA的基因缺失会减弱Mtb在人类巨噬细胞中的生长，并且PtpA中和抗体的表达模拟了这种效果。我们鉴定出膜融合调节因子VPS33B是PtpA的底物。VPS33B和PtpA在感染Mtb的人类巨噬细胞中共定位。PtpA的分泌与活性磷酸化的VPS33B相结合可抑制吞噬体-溶酶体融合，这一过程在Mtb感染中受阻。这些结果表明PtpA对Mtb在细胞内的持续存在至关重要，并确定了一条被Mtb灭活的关键宿主调节途径。
